൯ get ready for any audit? we hope to shed some light on ... you audit ready...

Are you Audit Ready?

Presenter

Presentation Notes

We get a lot of questions about audits. Who does them? Why? What do they look at? Is there anything I can, or should, do to get ready for any audit? We hope to shed some light on those matters with this presentation.

A P R E S E N T A T I O N B Y : T U L A N E C L I N I C A L T R A N S L A T I O N A L U N I T

A N D T U L A N E H U M A N R E S E A R C H P R O T E C T I O N O F F I C E

Audit Ready?

Presenter

Presentation Notes

This is a presentation of both the Louisiana Clinical and Translational Science Center and the Tulane Human Research Protection Office.


Produced by: The Tulane Clinical Translational Unit

Director: Roberta McDuffie, ACNS-BC, MSN, BSBA, CHRC

The Tulane Human Research Protections Office

Director: Roxanne R. Johnson, MSPH, CHRC

The Research Compliance Office

Tulane Research Compliance Officer: Brian J. Weimer, Esq.

Presentation Outline

Research Noncompliance Audit Readiness FDA Audits Pop Quiz! OHRP Audits NIH Clinical Trials Monitoring Audits

Presenter

Presentation Notes

We may not get through all the slides; however, this presentation will be posted to the Tulane IRB/HRPO website as a resource on being “Audit Ready” and what to expect based on the entity conducting the audit.

Noncompliance Defined and Discussed


Presenter

Presentation Notes

In discussing the subject of Audits, it is important that everyone have a clear definition of noncompliance, in the research context. So it seems that the logical place to begin is with that definition and a little information about noncompliance.

Noncompliance Definition

Any failure to follow 45 CFR part 46 (Code of Federal

Regulations - including any applicable subparts), the requirements or determinations of the IRB or the provisions of the IRB- approved research study

Can occur as a result of performing an act(s) that

violate(s) requirements Can also occur as a result of failing to act when

required

Presenter

Presentation Notes

45 CFR part 46 describes the basic Health & Human Services (HHS) Policy for Protection of Human Research Subjects. It is important to stop for a minute here to discuss the issue of noncompliance. Most, if not all, researchers have matters of noncompliance come up in their research. No one mean to, but everyone makes mistakes. Protocol deviations are noncompliance. Sometimes, researchers and their staff feel that the terms “noncompliance” and “protocol deviations” connote “bad behavior”. This is not true. Everyone, even the federal government, understand incidences of noncompliance. It happens. The most important matter is (1) that you catch it yourself, if possible and (2) that you repair it and, if necessary, report it in a timely fashion. More about that later.

Serious Noncompliance

Continuing Noncompliance

Failure to follow regulations and policies per Tulane SOPs

Failure to follow IRB

determinations and (in the judgment of the convened IRB) increases risks to participants decreases potential benefits, or compromises integrity of the HRPO

Research conducted without

prior IRB approval = Serious Non-Compliance

Pattern of Noncompliance (in the judgment of the RCO or convened IRB) that suggests a likelihood instances of noncompliance will continue without intervention

Includes failure to respond to a

request to resolve an episode of Noncompliance

What are the types of Noncompliance?

Presenter

Presentation Notes

Be aware that the regulations do not specifically define either “Serious Noncompliance” or “Continuing noncompliance”, however, HHS provides examples of both.

Minor Noncompliance

Actions or activities associated with conduct or oversight of research involving human subjects - fails to comply with either IRB-approved research plan,

or federal regulations or

institutional policies governing human subject research

That Does Not /Did Not…

Harm or increase risk to subjects

Cause negative change in

subjects’ welfare Significantly impact

integrity of the data Result from deliberate

misconduct by member of research team

Presenter

Presentation Notes

This is a pretty clear definition of what might be thought of as Minor Noncompliance, usually reportable as “protocol deviations”.

Examples of Minor Noncompliance

Change in study team members without IRB approval (not including PI)

Change in questionnaires without IRB approval Missed laboratory test, later obtained Changing schedule of study visits without IRB

approval Essentially, protocol deviations

Serious Noncompliance

Actions or activities associated with conduct or oversight of research involving human subjects - fails to comply with either IRB-approved research plan,

or federal regulations or

institutional policies governing human subject research

That Does…

Harm or increase risk to subjects

Cause a negative change

in subjects’ welfare Significantly impact the

integrity of the data Result from deliberate

misconduct by a member of the research team

Presenter

Presentation Notes

Again, same definition WITH ONE IMPORTANT DIFFERENCE, the noncompliance causes… (read bullets)

Examples of Serious Noncompliance

Conduct of research involving interactions/interventions with human subjects without IRB approval

Enrolling a subject failing to meet inclusion/exclusion criteria, placing subject at greater risk

Allowing IRB approval of study to expire and continuing study activities during a period of expiration

Failing to obtain or document informed consent

Examples of Serious Noncompliance/ Continuing Noncompliance

Failing to maintain copies of informed consent forms Conducting a procedure without IRB approval; failing to

perform a procedure that may impact subject safety or data integrity

Failure to follow safety monitoring plan Enrolling subjects after IRB approval has expired Failing to report serious adverse events or unanticipated

problems to the IRB Multiple minor Noncompliance issues can be considered


Possible Consequences of Serious/Continuing Noncompliance

Reporting to Federal agencies (OHRP and FDA) and funding agencies (NIH)

Mandatory re-education, Independent certification of the PI and study team

Removal of PI from study and/or all studies

Tarnished reputations

Loss of funding or sponsorship

Debarment from research

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Presentation Notes

It’s always important to cover to possible consequences of failure to comply with the regulations to facilitate an appreciation for their level of importance.

Additional Issues


Failing to follow reporting requirements

Corrective Action Plans

Preventive Action Plans

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Presentation Notes

I said we would talk a bit more about the subject before moving on. Here it is: Noncompliance happens. It’s a reality of conducting regulated research. Document the event, report it timely to the IRB and sponsor (if appropriate), include a well thought-out proposed corrective action plan when reporting the noncompliance, and complete the corrective action plan approved by the IRB and sponsor (if appropriate). Regulatory Agencies conducting an audit will be checking that noncompliance was timely reported and that appropriate follow-up actions were completed.

Are You?

Audit Ready

Audit Ready

Who can audit my research? (as applicable)

FDA (U.S. Food and Drug Administration)

OHRP (Office for Human Research Protections, Department of Health and Human Services)

DOD (Department of Defense) NIH (National Institutes of Health {and associated entities})

Other federal and state sponsoring agencies VA (U.S. Department of Veterans Affairs) DEA (Drug Enforcement Agency)

Private Sponsors Local IRB/HRPO Research Compliance Office

Be Prepared

Research Study File Maintenance Keep files organized at all times Retain all correspondence from

Sponsor Monitors Study subjects IRB Letters, faxes, emails, memos, telephone contacts

Retain all test articles and accountability records Retain shipping receipts, screening and enrollment logs, dispensing logs Maintain regulatory binder

Audits can be unannounced or scheduled: Always be Audit Ready

FDA

Food and Drug Administration

Be Prepared

FDA Inspection Triggers (increase the chance of an FDA audit)

Studies with High Enrollment, where test article approval is pending

Studies with Few or No Adverse Events PIs who have received a FDA form 483 in the past Studies where other sites have had problematic inspections

Presenter

Presentation Notes

FDA audits involve clinical trials involving drugs or devices. A number of other types of research products including biologics, foods, human tissue for transplant, radiological medicine and veterinary medicine may be conducted under FDA review.

FDA 1572

Signing 1572: PI commitment… …to be responsible for the study by

Following federal guidelines for the protection of human subjects

Interactions with IRBs involved Adhering to IND application regarding details of

adverse event reporting and recordkeeping Being AUDIT READY

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Presentation Notes

The 1572 describes the PI’s responsibilities in the research study.

FDA Form 1572

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Presentation Notes

Example of a 1572

FDA Warning Letters (2015)

Most common cause: Protocol Noncompliance (Failure to conduct in accordance with investigational plan)

Examples Missing safety labs

No documentation of reasons for missed subject visit/test

Failure to ensure and document eligibility criteria were met

Making changes to the protocol without first obtaining IRB approval

Presenter

Presentation Notes

The number one cause of FDA warning letters in 2015 is Protocol Noncompliance


Inadequate Case Histories – Failure to maintain adequate and accurate case histories with respect to data or informed consent Examples

Failure to complete case report forms (CRFs) Inadequate or non-existent source documentation to

support data in CRFs Lack of properly documented informed consent and

lost records Failure to document timely review of adverse events

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Presentation Notes

The number two cause is Inadequate Case Histories


Failure to obtain informed consent in accordance with 21 CFR part 50 EXAMPLES

No consent before administration of test article Missing consent forms Participants did not sign and date consent Most recent IRB-approved consent was not used Re-consent was not obtained or not obtained in a timely manner Consent did not contain required elements Inappropriate time period between consent signature and first study

procedure No documentation of time of informed consent process (to show that

the process took place before research procedures began) Improper consent of non-English speaking subjects

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Presentation Notes

Number three…

First Rule of Medicine Applies to FDA Review

If it wasn’t documented, it wasn’t done!

FDA Inspections

Intention of Inspections

Determine compliance with federal regulations and adherence to guidelines

Verify validity and integrity - clinical data submitted in applications for approval

Assure that rights and welfare of subjects participating in clinical studies are being protected

Presenter

Presentation Notes

The FDA is clear about the intention of their inspections.

In Case of a Notification of Audit

Immediately review your institution’s Standard Operating Procedures (SOPs) for audits

Contact the Human Research Protection Office (HRPO) and Research Compliance Office (RCO)

Consult and adhere to your institutional your departmental policies and procedures regarding impending audit

Presenter

Presentation Notes

HRPO/RCO will assist in making sure you are “audit ready”. The self audit tool to which we refer is available on Tulane’s HRPO website. However, it can be accessed by those outside of Tulane. In addition, in other institutions, your own office of research protections may be able to assist you with a similar tool. Some self-audit tools will be available from the Tulane CTU as well.

In Case of a Notification of Audit

Retrieve and assemble requested trial-related records

Notify study-delegated personnel about the date, time and occurrence of the inspection PI Department Representative Sponsor Contact Project Manager and/or

Lead Study Coordinator Contact the HRPO and RCO Investigational Pharmacist

PI must be available in person during the Inspection

If the PI is unavailable on the scheduled inspection date, the inspection must be re-scheduled

A request to re-schedule must be made in a timely manner

Preparing for the FDA Inspection

You must cooperate with any FDA Inspection

All study personnel must be available to answer questions for which they have direct knowledge

Secure a room for the Inspection that can be locked and available for more than one day, if necessary

Designate a “documents” person to assist in preparation for the Inspection and for the actual Inspection

Preparing for the FDA Inspection

Lead Study Coordinator or Project Manager: retrieve and assemble all study-related records SOPs

Regulatory records

CRFs, monitoring reports

Source records

Test article accountability records

Lead Study Coordinator: organize all study-related files, arrange logistics, and prepare for the audit

PI and department representative function as liaison/escort for FDA Inspectors, facilitating requests

Conducting the Inspection - Role of the PI

Greet FDA Inspector(s) Verify ID/Credentials FDA Inspector should provide

FDA 482 (unless this is a criminal investigation)

If no FDA 482 is provided, notify General Counsel immediately

Provide a tour of facility Assist as needed

Provide requested records. Make 2 copies of each record requested – one for FDA, one for site

Ensure that each question is answered by a knowledgeable person

Accompany FDA inspector(s) at all times, unless they are in conference room, reviewing records

Arrange for follow-up as required for unanswered questions or outstanding documents

Presenter

Presentation Notes

FDA will issue a citation for failure of the researcher to verity ID/Credentials. The Auditor will have access to protected health information as well as subjects’ confidential information, and the auditor will want to ensure that the researcher is complying with privacy and confidentiality requirements by not allowing access to such information without proper screening. For all records requested by the FDA, review the 2nd copy that you made for any potential issues, and take steps to correct such issues when identified.

FDA Form 482

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Presentation Notes

FDA 482

Conducting the Inspection – Role of Liaison

Take notes concerning progress of inspection

Provide requested records, make photocopies for FDA and the clinical site

Document any line of questioning pursued by PI and FDA Inspector, including issues that remain unresolved and steps taken to resolve Try to resolve any such

unresolved issues while the Inspection is still occurring

Arrange any interviews requested by FDA inspector(s) and escort FDA Inspector(s) if they request to go to specific sites

Document name and title of all persons interviewed by FDA and date and time of interview

Post-FDA Inspection

PI or Liaison should request an end-of-day discussion during each day of inspection with FDA Inspector to review preliminary findings

Document any questions whose answer could not be provided along with follow-up to request appropriate information

If PI receives an FDA 483 (report of observations) after audit, PI should consult General Counsel on how to respond and provide sponsor with an opportunity to assist in response

Citations, used for the 483, are maintained in a database and are reviewed, edited and updated on a periodic basis. Citations relate to a Code of Federal Regulations (CFR) reference, and there may be many citations for a single CFR reference. To create an FDA Form 483, citations are selected from the pre-established system or database. The Long Description is entered into the FDA Form 483, ensuring uniformity of presentation, then specific information related to the observation may be entered, and the citations may be ranked by significance on the 483.

Presenter

Presentation Notes

FDA 483

483

Number of 483s Issued from the System* Inspections fiscal year 2015 Center Name

483s Issued

Biologics 123

Bioresearch Monitoring 283

Devices 1008 Drugs 678 Foods 2300

Human Tissue for Transplantation 81

Parts 1240 and 1250 66 Radiological Health 17 Veterinary Medicine 294

Sum Product Area 483s from System* 4850

Actual Total in System 483s** 4751

FDA Form 483 notifies institutions’ management of objectionable conditions – not all-inclusive

Institutions responsible for corrective action addressing cited objectionable conditions

Form 483s are discussed with a management at conclusion of the inspection

Presenter

Presentation Notes

FDA 483 purpose and occurrences in 2015

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Biologics

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Bioresearch%20Monitoring

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Devices

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Drugs

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Foods

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Human%20Tissue%20for%20Transplantation

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Parts%201240%20and%201250

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Radiological%20Health

http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Veterinary%20Medicine

Post-FDA Inspection

PI or designee must send a copy of FDA 483 to sponsor’s project manager, HRPO, RCO, and General Counsel, as well as submitting the FDA 483 for IRB review via IRBNet

PI must arrange a meeting to discuss findings with General Counsel, HRPO, RCO, and other offices, as necessary

PI prepares a written response with input from appropriate persons to any observations noted in FDA 483; response should be sent to FDA within time specified (usually 15 days)

Presenter

Presentation Notes

Directions for handling of FDA 483

Post-FDA Inspection

Include in PI’s response Address each observation and

steps implemented to remedy observation and prevent future occurrences

Response should be factual and should be respectful, professional and cooperative

PI should attempt to obtain a copy of official FDA investigator’s field audit report under the Freedom of Information Act (FOIA) request This request can be made at

the conclusion of the 483 response

FDA does not normally respond to such requests until the matter is formally closed

Get help from RCO and Office of General Counsel

QUIZ: Are You Ready?

What is the most common finding during a FDA Inspection?

Failure to obtain informed consent in accordance with the regulations

Failure to protect rights, safety and welfare of study participants under care of the principal investigator

Failure of investigator to conduct a study according to protocol

Failure to maintain adequate and accurate case histories

http://foreresearch.com/news/ready-fda-inspection-take-quiz/


Anything you talk about with the auditors is official discussion and can be used as part of the Establishment Inspection Report?

True False



You may offer your FDA Inspector lunch, validated parking, etc. as a courtesy when they are performing an investigation.

True False



What is the best way to prepare your study staff for a FDA Inspection?

Have written SOPs that detail processes on all research procedures, documentation methods, and individuals responsible for each activity

Routinely conduct “mock audits” Ensure that all study documents

are organized, complete and current

Identify which staff members are responsible for specific areas of the study

Ensure staff understand the protocol completely

All of these apply



Your sponsor is a key resource during a FDA Inspection.

True False



What is not considered an obligation of the Principal Investigator, according to the FDA?

Appropriate delegation Follows protocol Obtains required IRB

approvals Patient recruitment Appropriate informed

consent process and documentation



What prompts a “for cause” FDA inspection?

Complaints filed in question of whether the rights and safety of patients are at risk

Complaints filed in question of whether integrity of study data has been compromised

Sponsor concerns All of these apply http://foreresearch.com/news/ready-fda-inspection-take-quiz/


It is best to have one point person who will escort the inspector at all times and answer any questions.

True False


OHRP

HHS Office of Human Research Protections

OHRP Jurisdiction

Research involving human subjects conducted or supported by U.S. Department of Health and Human Services that is not otherwise exempt

and

Non-exempt human subject research covered by Assurance of Compliance “HHS human subject protection regulations and policies require that any institution

engaged in non-exempt human subjects research conducted or supported by HHS must submit a written assurance of compliance to OHRP. The Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP. FWAs also are approved by the Office for Human Research Protections (OHRP) for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (also known as the Common Rule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.”

Presenter

Presentation Notes

As an entity engaged in human subject research funded by HHS, Tulane is require to file an assurance that Tulane complies with the federal regulations, including the Common Rule.

For Cause Not For Cause

Responds to substantive allegations or indications of non-compliance in HHS-supported research or under an applicable assurance; usually through correspondence (>90%)

Assesses institutional compliance with 45 CFR 46 in absence of specific allegations; can be partially “for cause” (previous compliance problems or vague allegations); often through site visit (~1/3)

OHRP For Cause vs. Not for Cause

Presenter

Presentation Notes

OHRP can and does audit/review the IRB, in addition to specific research studies.

OHRP Compliance Oversight Investigation – For Cause

Receive allegation or indication of Noncompliance Determine whether or not OHRP has jurisdiction

over the study OHRP to send written inquiry to appropriate

institutional officials OHRP will review institution report and relevant IRB

documents (sent by institutional officials/response)

OHRP will communicate with institution as needed (correspondence/telephone interviews/site visit)

OHRP will issue final determinations

OHRP Compliance Oversight Investigation – Not For Cause

OHRP can investigate institutions within its jurisdiction

OHRP will send written inquiry to appropriate institutional officials

OHRP will review institutional report and relevant IRB documents (sent by institutional officials/response)

OHRP will communicate with institution as needed (correspondence/telephone interviews/site visit)

OHRP will issue final determinations

OHRP - Opening a Compliance Case

Possible OHRP responses to initial institutional response OHRP may ask additional questions; express concerns OHRP may conduct phone interviews OHRP may conduct an on-site evaluation of human subject

protections

Presenter

Presentation Notes

Once the institution has responded to the initial notification, these are the possible “next steps”.

Preparing for an OHRP Inquiry

Notify Institutional Officials (IO, HRPO, RCO, and General Counsel)

Review “OHRP Recent Compliance Oversight Determinations” http://www.hhs.gov/ohrp/compliance-and-reporting/determination-letters/2016/index.html

Re-review regulations, particularly the subparts Review OHRP guidance documents Review Institutional SOPs Ensure clear and consistent documentation of IRB

activities Designate one contact person for compliance oversight

coordinator who will coordinate requests, questions, etc.

Presenter

Presentation Notes

As previously discussed, the audit tool is available on the Tulane HRPO website but similar tools may be available at individual institutions.

http://www.hhs.gov/ohrp/compliance-and-reporting/determination-letters/2016/index.html

http://www.hhs.gov/ohrp/compliance-and-reporting/determination-letters/2016/index.html

For Cause Not For Cause

Triggered by open compliance case

Site visit team includes OHRP attorney, 2 – 5 OHRP staff, 2 – 4 outside consultants

Visit lasts 3 – 4 days Dual focus on allegations

and systemic protections

No open compliance case Site visit team consists of

1 – 3 OHRP compliance staff, plus 1 – 3 outside consultants

Visit lasts 2 – 3 days Focus on systemic

protections

OHRP Site Visits - Two Types

OHRP’s Preparation for a Site Visit

Request protocols and other documents to be reviewed

Describe/name officials/groups to be interviewed Provide ample lead time to institution; work

cooperatively to set schedule

Presenter

Presentation Notes

You will receive notification of the items requested by OHRP.

After OHRP Site Visit

OHRP will send a letter with official findings and additional questions/concerns within a few weeks

Institution will be asked to respond with corrective action plans in approximately 6 weeks

OHRP will evaluate adequacy of corrective action plans

Possible Determinations

and/or Outcomes

Compliance Oversight Investigation

Possible Determinations/Outcomes (1)

Protections under an institution’s Assurance are in compliance

Protections under an institution’s Assurance are in compliance, but recommended improvements have been identified

Noncompliance identified, corrective actions required

Noncompliance identified, Assurance restricted/suspended pending required corrective actions


Noncompliance identified, OHRP approvals of Assurance withdrawn

OHRP may recommend to appropriate HHS officials or PHS agency heads that An institution or investigator be temporarily suspended or

permanently removed from participation in specific project Peer review groups be notified of an institution’s or an

investigator’s past noncompliance prior to review of new projects


OHRP may recommend that institutions or investigators be declared ineligible to participate in HHS-supported research (debarment). Debarment initiated in accordance with procedures specified at 45 CFR Part 76.

Conducting the

Audit

NIH Clinical Trials Monitoring Branch

NIH Clinical Trials Monitoring Branch

One of the world’s largest publicly-funded sponsors of clinical trials

NIH must ensure that research data generated under its sponsorship are of high quality, reliable and verifiable

Auditing is conducted to determine whether trial-related activities were conducted, dates recorded, analyzed and accurately reported according to the protocol, sponsor’s SOPs, GCP and the applicable regulatory requirements

Presenter

Presentation Notes

It is a snapshot in time, commonly an on-site process, and consists of reviewing a subset of study participants on a trial

NIH Audit – Source Documents

IRB documents and ICFs Drug accountability record forms/logs for

imaging/radiopharmaceutical agents Inpatient and outpatient medical records Study flow sheets Protocol Enrollment tracking sheets Patient diaries/calendars

NIH Audit Findings

Review and evaluate the following Documentation and conformance to IRB and ICF

requirements Pharmacy operations and use of drug logs Individual subject cases

Each component will independently be assigned an assessment of Acceptable Acceptable; Needs Follow-up Unacceptable – Re-audit Required

NIH Audit - Examples of Major Deficiencies

IRB-related Issues Protocol never approved by IRB Initial IRB approval documentation missing Registration and/or treatment of subject prior to full IRB approval Registration of subject on protocol during period of delayed approval

or during temporary suspension Missing approval Expired approval Internal reportable adverse events reported late or not reported Lack of documentation of IRB approval of amendment on greater

than minimal risk research Failure to submit timely external safety reports

NIH Audit - Examples of Major Deficiencies

Informed Consent Omission of one or more risks/side effects Omission of one or more revisions per amendment Omission of one or more required informed consent elements Changes made to the informed consent not approved by IRB Multiple cumulative effects of minor problems for a given ICF

NIH Audit Findings - Assessing Deficiencies

Acceptable No deficiencies Few LESSER deficiencies A major deficiency that was discovered and corrected prior to the audit

Acceptable; Needs Follow-Up Major deficiency identified during the audit

but not addressed or corrected prior to the audit Multiple lesser deficiencies

Presenter

Presentation Notes

This describes the “ranking” of various types of deficiencies for NIH.

Assessing Deficiencies (cont’d)

Unacceptable Multiple major deficiencies identified A single major flagrant deficiency found Excessive number of lesser

deficiencies identified

NIH Audit - Accountability of Investigational Agents and Pharmacy Operations

Control Dispensing Area/Pharmacy Direct receipt of agents Appropriate storage and security Dispensing as required by protocol Overall inventory control Final disposition of agents

Satellite Dispensing Area/Pharmacy (same as above)

Imaging Studies Pharmacy Review – based on compliance/non-

compliance measures, due to complexity

NIH Audit - Review of Subject Case Records

Approximately 10% of subjects reviewed for major and lesser deficiencies Properly signed and dated consent forms Established Eligibility (Inclusion/Exclusion criteria review for each

subject)

Correct treatment and treatment sequence Evaluation of disease outcome Adverse events relative to treatment General quality of data collected

NIH Audit - Major Deficiencies (examples)

Informed Consent Document Consent form document missing Consent form document not signed and dated appropriately Translated form not signed and dated by study participant Consent form not signed by patient prior to enrollment Consent form used not current IRB-approved version at time

of registration Consent form is not protocol-specific Consent form does not contain updates or information

required by IRB Re-consent not obtained as required

NIH Audit Major Deficiencies (examples)

Subject Eligibility Review of documentation available at the time of audit

confirms study participant did not meet all eligibility criteria and/or eligibility requirements were not obtained within the timeframe as specified by the protocol

Documentation is missing; unable to confirm eligibility

Major Deficiencies (examples)

Treatment Incorrect treatment/intervention used Additional treatment used/not permitted by protocol Dose deviations, modifications, or incorrect calculations Dose modifications/treatment interventions not per protocol Treatment/intervention incorrect or not documented

adequately Timing/sequencing of treatment/intervention not per protocol Unjustified delays in treatment/intervention

Major Deficiencies (examples)

General Data Management Quality Recurrent missing documentation in study participant record Protocol-specific laboratory tests not reported or documented Protocol-specific diagnostic tests, including baseline

assessments, not done/not reported/not documented Frequent data inaccuracies Errors in submitted data Delinquent data submission

RESOURCES

https://acrpblog.org/2016/04/18/auditing-your-site-vendors-and-other-pointers-for-pis-who-are-new-to -research/

Title 21 CFR part 11 Title 21 CFR parts 50 & 56 Title 21 CFR part 312 & 312.62 Title 21 CFR part 812 & 812.140 ICH GCP Consolidated Guideline Part 4.9 ICH GCP Consolidated Guideline Part 5.15 http://www.yale.edu/hrpp/education/documents/Nonc

ompliance_122012.ppt

https://acrpblog.org/2016/04/18/auditing-your-site-vendors-and-other-pointers-for-pis-who-are-new-to%20-research/



http://www.yale.edu/hrpp/education/documents/Noncompliance_122012.ppt

http://www.yale.edu/hrpp/education/documents/Noncompliance_122012.ppt

RESOURCES

FDA Compliance Program Guidance Manuals 7348.811 & 7348.810

FDA Investigations Operations Manual http://foreresearch.com/news/ready-fda-

inspection-take-quiz/ https://wwwp.oakland.edu/Assets/upload/docs/Res

earch/2--D--Elyse-Summers-Audits-Part-1-The-IRB.pdf

http://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ctmb_audit_guidelines.pdf

HRPO Self Audit Tool



https://wwwp.oakland.edu/Assets/upload/docs/Research/2--D--Elyse-Summers-Audits-Part-1-The-IRB.pdf





https://www2.tulane.edu/asvpr/irb/upload/Investigator-Self-Assessment-Checklist-4.doc

Acknowledgements

We would like to acknowledge those people who assisted significantly in this presentation: Bonnie Katalenich Ellen Dauchy Gail Louis Ashanti Roberts Monique Teixeira Rachel Cruthirds